Dimethylated steroids and processes for producing same



United States tet DINIETHYLATED STEROIDS AND PROCESSES FOR PRODUCING SANIE Meyer Sletzinger, North Plainfield, and Walter A. Gaines, Rahway, N.J., assignors to Merck & Co., Inc., Rahway, NJ., a corporation of New Jersey No Drawing. Filed Oct. 1, 1958, Ser. No. 764,525

23 Claims. (Cl. 260-23955) This invention relates generally to new methods for making physiologically-active steroid compounds. More particularly, it is concerned with novel processes for preparing 6a,l6-dimethyl steroids of the pregnane series and with new steroid substances which are intermediates in such novel processes. Still more specifically, it relates to the synthesis of 6a,l6-dirnethyl-3,20-diketo-17,20-dihydroxy steroids of the pregnane series. Such compounds, when oxygenated at the ll-position exhibit a very high degree of cortisone-like anti-inflammatory activity. Still more specifically, this invention is concerned with methods for converting a a,6a-oxido-l6- methyl steroid to a 6a,l6-dimethyl steroid and with novel steroid intermediates produced therein.

6a,16 dimethyl-3,20-diketo-17u,2l-dihydroxy steroids oxygenated at the ll-position, and 21-esters thereof, such as 6u,l6u-dimethyl hydrocortisone; 6a,l6o-dimethyl prednisone and prednisolone; 6a,16a-dimethyl-9a-fiuoro prednisone and prednisolone; and 6a,16a-dimethyl-9efiuoro hydrocortisone and the corresponding l6B-methyl compounds possess extremely high anti-inflammatory activity, and are especially effective for the treatment of arthritis and related diseases since they have a minimal amount of undesired side effects at the effective dosage level. It is an object of this invention to provide a novel synthesis of such substances. It is a further object to provide a synthesis of these useful materials from a 16- methyl-Sa,6a-oxido-allopregnane. It is a still further object to provide novel Swhydroxy-GB,l6-ditnethyl-allopregnanes obtained as intermediates in this process. Other objects will be evident from the ensuing discussion of our invention and from the flow diagram hereinbelow.

The new processes and new steroid compounds of the invention are structurally depicted in flow chart 1, with respect to the preparation of 6a,16a-dimethyl steroid compounds. The same process is employed for making the corresponding 6a,16fi-dimethyl compounds from a Su,6a-oxido-l6fi-methyl steroid of the pregnane series (e.g. I, where the l6-methyl group is in the beta position).

FLOW CHART l /O-CH2 0-CH: H2C\ J) 1330 O- -O OCO CH: CH: Ton; Ton;

l l (3 DH CHI I II 2,940,968 Patented June 14, 1960 III IV R=group hydrolyzable to keto The starting materials in this process are 5u,6x-oxides of Formula I hereinabove. The 3-position of the steroid nucleus contains a substituent hydrolyzable to a keto group. We prefer to employ an ethylenedioxy radical to block the 3-keto group, although other groupings such as ketals, thioketals and other cyclic ket-als may also be utilized.

The initial step of our new process comprises the introduction of a 6-methyl substituent into the steroid nucleus by treating or reacting a 5a,6ot-oXido-allopregnane of Formula I with a metallo-organic methylating compound, and in particular with a methyl Grignard reagent. As the methylating agent, we prefer to employ a methyl magnesium halide such as methyl magnesium bromide or iodide. If desired, a small amount of activating agent such as iodine or copper chloride may be used to initiate the reaction. Cleavage of the Sofia-oxide and introduction of the 5a-hydroxy and -methyl substituents of Formula II is carried out in an inert organic solvent medium, preferably in the substantial absence of oxygen. Suitable solvents are benzene, toluene, ethyl ether, ben- Zeno-ether mixtures and the like. The methylation is preferably efiected at an elevated temperature and it is convenient to carry out the process at the reflux temperature of the solvent medium. Upon completion of the reaction, the 5a-hydroxy-6fi-methyl steroid is recovered by quenching the reaction mixture in the cold and isolating the steroid material from the organic solvent by extraction and crystallization techniques. In this fashion there are obtained steroids such as 6,3,16adimethyl-17-20,20-2l bismethylenedioxy 3 ethylenedioxy-allopregnan-Sa,11B- diol; 6 3,16u-dimethyl-l7-20,20-21 bismethylenedioxy-3- ethylenedioxy-allopregnan-Sa-ol; and 6,8,16a-dimethyl-17- 20,20-21 bismethylenedioxy-3-ethylenedioxy-allopregnanlI-one-Sa-Ol, and the corresponding 1613-methyl compounds.

"In the next step of this process, steroids of the general Formula H are treated with a dilute mineral acid or with anhydrous formic acid to remove the hydrolyzable substituent at the 3-position and regenerate a 3-keto group.

For this purpose, we prefer to employ -10% sulfuric acid, dilute hydrohalic acid or 98% formic'acid. The reaction is carried out preferably in an inert atmosphere, e.g.-nitrogen or carbon dioxide, at about 50-90 C. for a short period. From 15 minutes to one hour is ordinarily suflicient to acc'omplish the hydrolysis of the ketal group. Lower alkanols such as methanol, ethanol or isopropanol are satisfactory media for this step of the process, although other wate'rmiscible organic solvents stable under the reaction conditions could also be utilized.

In the third step of the synthesis of this invention a 5a-hydroxy-6/3-methyl allopregnane, structure HI hereinabove, is reacted with a base in order to remove the elements of water from the 4:5 positions of the steroid nucleus, generate the 4:5 double bond and epimerize the 6/3-methyl substituent to the alpha configuration. There is thus obtained a 3-keto-6u-methyl-A -pregnene having the structure IV. To effect this reaction, the steroid is treated in solution with a base, and preferably with a strong base. Alkali metal hydroxide such as sodium, potassium and lithium hydroxides are very suitable for this purpose, although other bases such as calcium hydroxide might also be used. The reaction is brought about at temperatures of about 50100 C. and is ordinarily substantially complete in 30to 90 minutes. Lower alkanols have been found particularly suitable as solvent media. According to this process there are produced methylated steroids such as 611,16l1-(O1' 1619) dimethyl-17-20,20-21 bismethylenedioxy-4-pregnen 3 one 1118-01; 6oz,16oz-(01' 16;3)-dimethyl 17-20,20-21 bismethylenedioxy-4-pregnene-3,11- dione and 6m,16a-(O1' 16,8)-dimethyl-17-20,20-21 bismethylenedioxy-4-pregnen-3-one. Such compounds may be converted to the parent steroids by removal of the 17-20,20-21 bismethylenedioxy moiety. This is accomplished by heating the bismethylenedioxy steroid with an acid such as 50% aqueous acetic acid or 60% formic acid.

"6u,16a-dimethyl cortisone and 6u,16a-dimethyl hydro cortisone (Formula V hereinabove, wherein R includes keto and hydroxy respectively) are themselves highly active anti-inflammatory agents. They may be converted to 6a,16a-dimethyl prednisone; 6a,16u-dimethyl prednisolone; the 9a-halo derivatives thereof; 611,160:- dimethyl 9a-halo hydrocortisone and 604160: dimethyl 9u-halo cortisoneas described in copending application Serial No. 683,923, filed September 16, 1957.

Likewise 6a,-16 8-dimethyl cortisone and 6u,16;9-dimethyl hydrocortisone have a very high degree of antiinflammatory activity. They are useful as antiinflammatory agents, and as intermediates .in the synthesis of 61,165 dimethyl9a-halo hydrocortisone; 6a,16fl-dimethyl- 9a-halo cortisone; 6a,16,8-dimethyl prednisone and prednisolone, and the 9a-halo derivatives'thereof, all of which 6u,16}9-din1ethyl steroids are claimed in copending application Serial No. 764,523, filed on even date herewith.

The 6a,l6-di-methyl-ll-desoxy steroid compounds produced. according to the methods of this invention are converted to the corresponding ll-oxygenated substances by microbiological hydroxylation techniques such as by fermentation'with ll-hydroxylating strains of Curvularia lunala.

'I'hUS,.6oz,16oc-'dim6thyl substance S (Formula V wherein R includeshydrogen) may be converted to 60:,16a-dimethyl hydrocortisone by treatment with an 11,B-oxygenating microorganism such as known strains of Curvularia lunata. -*In an additional embodiment of our invention, 613,16- dimethyl-l7-20,20-21 bisniethylenedioxy-S'-ethylenedioxy- Sat-o1 steroids of'For-mula II hereinabove may be con verted directly to 6d,16-dirnethyl-3,20-diketo-l7a,2ladihydroxy steroids of Formula V hereinabove by treatment 4 with an acid hydrolyzing agent under reaction conditions suitable for removal of the 17-20,20-21 bismethylenedioxy moiety. This embodiment of the invention, wherein Compound II is converted directly to Compound V is brought about by heating a steroid of Formula II with aqueous acetic acid or 60% formic acid.

The following examples are given for purposes of illustration and not by way of limitation:

EXAMPLE 1' 66,16a-dimthyl-17-20,20-21 bismethylenedioxy-i-ethylenea'ioxy aIIOpregnan-SaJIfi-dioI (II) 7 To a. solution of 250 mg. of 16a-methy1-17-20,20-21 bismethylenedioxy 3 ethylenedioxy 5u,6a-oxido-allopregnane-llB-ol (I) in' 60 ml. of dry benzene under nitrogen is added 2.33 ml. of 3 M methyl magnesium bromide in ether. The mixture is heated at 70 C. under nitrogen for five hoursq; After cooling to 0-5? C., 5.6 grams of ammonium chloride in 56 ml: of water is added over about a 20-minute period. The benzene is separated and the. aqueous layerextractedrwith two 20 ml. portions of benzene. The combined benzene solutions are washed neutral with water, dried with magnesium sulfate and concentrated to dryness. The 63,16a-dimethyl-17-20,20-21 bismethylenedioxy-3-ethylenedioxyallopregnan-SmJlB-diOl thus obtained-is normally used in the next step of the process without further purification. On recrystallization from ether or benzene it is obtained substantially pure, melting point 178482? C.

EXAMPLE 6 ,1sa-di erh -u-zogo-n bismthyleiiadioxyaillopreg- A solution oftwo grams or 6fi,16a-dimethyl-17.-20,20-21 bismethylenedioxy 3 ethylenedioxy-allopregnan-Sa,l1B- diol in 100 ml. of methanol is purged four times with nitrogen. 10.9 ml. of 8% sulfuric acid (v./v.) is

. added, the mixture purged four times with nitrogen and then heated at reflux under nitrogen for 35 minutes. The mixture is cooled to 0-5 C. and with'cooling and good agitation a solution of 10.9 grams of sodium carbonate in 300 ml. of water, is added. f The gummy 'precipitate is extracted with chloroform, washed with water and concentrated in vacuo to dryness. The mostly crystalline 6/3,16a-dimethyl-17-20,20-21 bismethylenedioxy-allopregnan-S-one-hJlB-diolthus obtained'is used directly in the nextreaction. It may be recrystallized from methanol or ethanol to give substantially pure material, melting point 235-239 C. a r

' EXAMPLE 3 6a,]6u dimethyl 17 20,20 21 bise'mthylenedi oxy-4- pregnen-ione-I 113-01 (IV) A solution of two grams of 6fl,16a-dimethyl 17-20,20- 21 bismethylenedioxy-allopregnah-B-one-5a,-1IB-diol in nil. of methanol is purged four times with nitrogen and then 4.2 ml. of 5% potassium hydroxide in methanol is added. After purging four times again, the solution is then refluxed under nitrogen for one hour. The solution is then cooled to 20 C. and acidified with a .few drops of glacial acetic acid. 25 ml. of water is added and the solution concentrated. in vacuo until essentially methanol-free. The slightly yellow. crystalline product thus obtained is filtered, washed with water and dried to give 6a,16u-dimethyl-17-20,20-21 bismethylenedioxytpregnen-3-one-1 1,6-01, melting point 270-275 C.

7&3, 2420, 13% 302 On recrystallization from methanol the material melts at 275-280 C.

- EXAMPLE 4 6a,la-aimethylhydrocortisone (V) 60% formic acid is purged six times with nitrogen and then heated on a steam bath at about 93-95 C. for 15 minutes under nitrogen. The compound is completely in solution after about five minutes. The solution is then cooled in an ice bath and 100 ml. of water added. Twenty grams of sodium carbonate are added slowly over 20 minutes to give a gummy precipitate which is extracted with chloroform. The chloroform solution is washed acid free with saturated sodium bicarbonate solution and then washed with Water. The chloroform is removed in vacuo and the residue flushed with 20 ml. of methanol and concentrated in vacuo to dryness.

The solid material thus obtained is dissolved in 45 ml. of purified methanol and purged six times with nitrogen. After adding 1.43 ml. of 0.21 M sodium methoxide in methanol, the solution is stirred for seven minutes at 20-25 C. under nitrogen. The solution is acidified with 3-4 drops of acetic acid, 5 ml. of water and 500 mg. of Darco G-60 charcoal added and the mixture stirred at room temperature for 20 minutes. After filtering off the carbon, 40 ml. of water is added and the solution concentrated in vacuo until essentially methanol free. The product is filtered and dried to give 6m,16cz-dim6thylhydrocortisone, melting point 201-209 C.

Recrystallization from ethyl acetate gives analytically pure material, melting point 239-242 C.

Al 2420, E% 391 EXAMPLE 5 65,160; dimethyl-17-20,20-21 bismetlzylenedioxy-3-ethylenedioxy-allopregnan-I 1 -ne-5-a-0l 200 mg. of 16a-methyl-17-20,20-21 bismethylenedioxy- 3-ethylenedioxy-5a,6a-oxido-allopregnan-1l-one is dissolved in 47 ml. of benzene and the solution purged with nitrogen. To the resulting solution is added 1.86 ml. of 3 M methyl magnesium bromide, and the resulting mixture stirred at 70 C. in a nitrogen atmosphere for five hours. It is then cooled to 0-5 C. and 4.5 grams of ammonium chloride in 45 ml. of water added over a 20-minute period. The layers are separated and the aqueous layer extracted with a small portion of benzene. All of the benzene solutions are combined, washed with three 25 ml. portions of water, dried over magnesium sulfate and concentrated to dryness in vacuo. The resulting 6p,16u-dimethyl-l7-20,20-2l bismethylenedioxy-3- ethylenedioxy-allopregnan-l 1-one-5 11-01 is used in the next step of the process Without purification.

EXAMPLE 6 6a,]6zx dimethyl-17-20,20-2J bismethylenedi0xy-4-pregnene 3,11-a'i0ne (a) 100 mg. of the product obtained as in Example is dissolved in 5 ml. of methanol and the solution purged with nitrogen. 0.4 ml. of 8% aqueous sulfuric acid is then added and the mixture is refluxed for about 35 minutes in a nitrogen atmosphere. At the end of this time, the solution is cooled to 0-5 C. and treated with 0.4 gram of sodium carbonate in 12 ml. of water. The sodium carbonate solution is added slowly over a tenminute period. 65,16a-dimethyl-17-20,20-21 bismethylenedioxy-allopregnan-3,11-dione-5a-ol precipitated at this stage of the process. The slurry is cooled and the solid product recovered by filtration.

(b) The material obtained in part (a) of this example is dissolved, without further purification, in 5 ml. of methanol and to this solution is added 0.2 ml. of 5% methanolic potassium hydroxide. The alkaline solution is refluxed under nitrogen for one hour. It is then chilled and acidified with about three drops of glacial acetic acid. The solution is then concentrated in vacuo to remove the methanol. The residual solid is dissolved in chloroform and washed with sodium bicarbonate solution and water. The chloroform solution is dried over magnesium sulfateand concentrated to dryness in vacuo. 6a.,16u-di- 6 methyl-17-20,20-21 bismethylenedioxy-4-pregnene 3,11- dione is obtained as a yellow oil which crystallized on standing,

are? 2380, 12% 261 This latter compound is converted to 6a,l6u-dimethyl cortisone by heating with 60% formic acid at about C. for 15 minutes.

EXAMPLE 7 6,6,16a-dinzethyl-1 7-20,20-21 bismethylenedioxy-allopregnan-3,1 1 -di0ne-5ot-ol mg. of the product of Example 5 is dissolved in 5 ml. of 98% formic acid and the mixture allowed to stand at room temperature for 2 /2 hours. At the end of this time 5 ml. of chloroform is added and the entire mixture poured into 25 ml. of water. The chloroform layer is separated, washed with sodium bicarbonate and water, dried over magnesium sulfate and concentrated to dryness in vacuo. The residual 6B,16oz-dimethyl-17-20,20-2l bismethylenedioxy-allopregnan-3,1l-dione-5a-ol thus obtained may be used without further purification in the next step of the process [Example 6(b)].

When this process is carried out on 6,8,l6a-dimetl1yl- 17-20,20-21 bismethylenedioxy-3-ethylenedioxy-allopregnan-5a,llfl-diol, there is obtained 6,8,16u-dimethyl-17- 20,20 21 bismethylenedioxy-allopregnan-3-one-5a,11,3- diol.

EXAMPLE 8 oeJoa-dimethyl-l 7-20,20-2l bismethylenedioxy-3-ethylenedioxy-all0pregnan-5u-ol 65,160: dimethyl 17-20,20-21 bismethylenedioxy-zzllopregnan-3-0ne-5u-0l One gram of 6n,16a-dimethyl-17-20,20-2l bismethylenedioxy-3-ethylenedioxy-allopregnan-Set-ol in 45 ml. of methanol is purged with nitrogen and mixed with 5 ml. of 8% sulfuric acid. The resulting solution is refluxed in an inert atmosphere for 30 minutes and then cooled to about 50 C. An aqueous solution of five grams of sodium carbonate in ml. of water is then added with cooling and agitation. The resulting precipitate is extracted with chloroform. The chloroform extract is washed with Water and concentrated to dryness to give 6,8,l6a-dimethyl-17-20,20-21 bismethylenedioxy-allopregnan-3-one-5a-ol.

EXAMPLE 10 60,16a dimerhyl-17-20,20-21 bismethylenedioxy-4-pregnen-3-0ne One gram of 63,16a-dimethyl-17-20,20-21 bismethylenedioxy-allopregnan-3-one-5a-ol in 50 ml. of methanol is refluxed in a nitrogen atmosphere for one hour with 2 ml. of 5% methanolic sodium hydroxide. The solution is then cooled to about room temperature and acidified with glacial acetic acid. 15 ml. of water is added and the resulting solution concentrated to dryness in vacuo. The 6a,16a-dimethyl-l7-20,20-21 bismethylenedioxy-4- pregnen-3-one thus obtained may be purified by recrystallization from a lower alkanol.

3'27 V if] EXAMPLE 11 r A h L 6oz,16u-dimethyl-substance S EXAMPLE. 12

6u,16a-dimethyl hydrocortisone Approximately three liters of a cortisone medium hav ing the composition:

Grams Dextrose 50 Enzymatic lactalbumin digest 20 Corn steep liquor Distilled water to make lliter.

is sterilized for 30 minutes at 120 C. The medium is then inoculated with approximately 125 ml. of a vegetati e growth of a llfi-hydroxylated strain of Curvularia lunata and agitated for approximately 24 hours at a speed of 560 rpm. Air is passed in at the rate of 3 liters per minute, and the temperature maintained at 28 C.

At the end of the 24-hour period a sterile solution of approximately one gram of 6a,16u-dimethyl-substance S in 160 ml. of propylene glycol is added to the fermenting medium, and aeration and agitation continued as before for an additional 24 hours.

*At the end of this time, the fermentation broth is filtered and extracted with 3-15 ml. portions ofethyl acetate. After washing with aqueous sodium bicarbonate and water, the combined ethyl acetate extracts are concentrated to dryness in vacuo.. The 6a,16u-dimethyl hydrocortisone is recovered from the residual solid by chromatography on silica gel.

, The starting materials for the processes of this invention, i.e. the l6ot-methyl steroids of Formula I in the flow chart appearing hereinabove, are prepared from 16w methyl cortisone and 16a-methyl substance S by a process which comprises treatment of a chloroform solution of such pregnenes with formaldehyde in the presence of hydrochloric acid to give a 16a-methyl-17-20,20-21 bisinethylenedioxy-El-ketoA -pregnene, reaction of these latter'compounds with ethylene glycol in the presence of p- -toluene sul-fonic acid to produce a 16a-methyl-17-20,2.0-21 bismethylenedioxy 3 ethylenedioxy-A -pregnene, and treatment of such A -pregnenes with perbenzoic acid in benzene to produce a 16a-methyl17-20,20-21 bismethylenedioxy-Seethylenedioxy-5a,6a-oxido allopregnane of Formula I hereinabove. In more detail, these procedures, which are also described in the copending application of one of us, Serial No. 746,661, filed July 7, 1958, are as follows: I

24 grams of 16u-methy1 cortisone, 910 ml. of chloroform, 237 ml. of concentrated hydrochloric acid and 237ml. f-37"/ b formaldehyde are combined and stirred at room temperature for 70 hours. The chloroform layer is separated and the aqueous layer extracted with two 50 m1. portions of chloroform. The combined chloroform solution is then washed with two 200 ml. portions of water, 200 ml. of saturated sodium bicarbonate solution and 200 ml. of water.. The magnesium'sulfate dried chloroform solution is concentrated in vacuo to crystals, flushed'with 100 ml. of methanol to remove all the chloroform and then sufficient methanol to dissolve the crystals is added.' The methanol solution is concentrated in vacuo to a thick slurry and cooled to 0-5" C. After aging, the product is filtered, washed with two ml. portions of cold methanol and dried in vacuo at 50 Yield 17.52 grams, melting point 23 1236 C. (65%) A sample recrystallized from methanol melts at 244- 250 C.

17.5 grams of l6a-methyl-17-20,20-2l bismethylenedioxy-4-pr'egnene -3,ll-dione is dissolved in' 890 'ml. of benzene and then 45 ml. of ethylene glycol and 1.78 grams of p-toluene sulfonic acid monohydrate added. The mixture is heated at reflux with stirring for 17.5 hours, continuously collecting the water formed. The solution is cooled to 20 C. and washed with two 200 m1. portions of water, 200 m1. of saturated sodium bicarbonate solution and 200 ml. of water. The washes areback extracted with benzene and all the benzene solutions combined; The dried benzene solution is concentrated to dryness in vacuo to give .a mixture of crystals and oil. This mixture is refluxed with ml. ofetherfor one-half hour, cooled, filtered and washed with cold ether. There is obtained 16u-methyl-17-20,20-21 bismethylenedioxy-Elethylenedioxy5-pregnen-1l-one; melting point 211--216 C., on recrystallization from acetonitr-ile the melting point is 210-220 C.

A solution of 22.9 grams of 16a-methyl-17-20,20-21 bismethylenedioxy-3-ethylenedioxy-S-pregnen-1l-one in 200 ml. of benzene is added to 460 ml. of 0.325 M perbenzoic acid solution over about 30 minutes keeping the temperature 2 0-25 C. After 48 hours at room temperature, the solution is cooled'to 10 C. and with good agitation a 15% solution of sodium bisulfite added at less than 20 C. until a negative KI test is obtained. The aqueous phase is removed and the benzene washed acid free with 5% sodium bicarbonate and then washed with water. After drying, the benzene solution is concentrated in vacuo to yield 24.7 grams,

' M OK Mix.

The a-oxide, 16u-methyl-17-2'0,20-21 bismethylenedioxy- 3ethylenedioxy-Sa,6a-oxido-allopregnan-1l-one is eluted with 10% acetone in hexane to give material which when recrystallized from benzene-hexane melts at 236-243 C.

gHCn 50 A solution of 500 mg. of the 5a,6ot0Xid0 compound obtained above in 35 m1. of tetrahydrofuran and a solution of 750 mg. of sodium borohydride in 20 of water is purged six times with nitrogen stirred for 18 hours, the solution is cooled to 0-5 C. and a saturated solution of 4.7 grams of monobasic sodium phosphate added over about 15 minutes. The reaction is stirred for an additional 15 minutes. The slurry is then concentrated in vacuo to remove tetrahydrofurankeeping the tempera ture below 25 C. The slurry is.cooled, .filtered and washed with water until neutral. There is obtained-16- methy1-17-20,20-21 bismethylenedioxy-3ethylenedioxy 5a,6m-oxido-allopregnane-1119-01, melting point 280-291 C., [M11325 a When this series of reactions is carried outv on 16amethyl-4-pregnen-3,20-dione-17a,2l-diol ,(16a-methyl sub: stance S) in the same fashion as described for 16a-methyl cortisone, there is obtained l6u-methyl-17-20,20-21 bis methylenedioxy 3 ethylenedioxy 7 5a,6 oxido-allo p g i 1'6m-methyl cortisone, reported in 9 3160 (1958), is prepared in accordance with the following procedure:

A solution of 10.22 grams of methyl iodide in 50 ml. of ether is added to 1.73 grams of magnesium in 50 ml. of ether. To the resulting ethereal solution of methyl magnesium iodide, maintained under a nitrogen atmosphere, is added 0.045 gram of anhydrous cuprous chloride. To this mixture is added, over a period of about one hour, during which period the reaction mixture is stirred vigorously and maintained at approximately room temperature, a solution of about 5.6 grams of 16-pregnen- 3a-ol-l1,20-dione 3-acetate in 175 ml. of ether. A white granular solid separates during this addition. The resulting mixture is heated under gentle reflux for two hours after which the reaction mixture is cooled, and 125 m1. of saturated, aqueous ammonium chloride solution is added followed by 200 ml. of ether. The layers are separated, and the ethereal layer is washed with three 50 ml. portions of water. The washed ethereal layer is dried, and the solvent evaporated in vacuo to give a brown viscous oil. The latter material is heated for minutes at 60- 70 C. with a mixture of 25 ml. acetic anhydride and 25 ml. pyridine and acetylated product is purified by chromatography on acid-washed alumina followed by crystallization from petroleum ether to give approximately 1.5 grams of substantially pure 16a-methyl-pregnan-3mol-11,20-dione 3-acetate.

To a solution of 0.8 gram of l6a-methyl-pregnan-3 a-Oll1,20-dione 3-acetate in 40 ml. of methanol is added 1.5 ml. of concentrated aqueous hydrochloric acid and the resulting solution is stirred overnight at about 25 C. The reaction solution is evaporated in vacuo at 25 C. to a small volume, and the concentrated solution is poured into 50 ml. of ice water. The white solid which precipitates is recovered by filtration, washed with water and recrystallized from ethyl acetate to give 16amethyl-pregnan-3a-ol-11,20-dione.

A solution of 22 grams of 16a-methyl-pregnan-3a-ol- 11, -dione 3-acetate and one gram of p-toluene sulfonic acid in 250 ml. of acetic anhydride is heated at reflux under nitrogen for a period of approximately three days. Two grams of potassium acetate -(anhydrous) is added, and the volatile solvents are separated by distillation in vacuo. The residual material is extracted with benzene, and the benzene extract is filtered to remove insoluble material. The benzene extracts are evaporated to a volume of 100 ml. and petroleum ether is added to the cloud point. The resulting solution is adsorbed on 660 grams of acid-washed alumina; the alumina adsorbate is then washed with two liters of petroleum ether. The adsorbate is then eluted with 85:15 petroleum ether-ether mixture, and the first four liters of eluate are collected, and evaporated to dryness in vacuo to give a mixture of enol acetates containing 16a-methyl-l7(20)-pregnen-3a, 20-diol-l l-one 3,20-diacetate. This mixture of enolates, weighing approximately 14 grams, is dissolved in 50 ml. of benzene, an excess of perbenzoic acid is added, and the mixture is kept at about 25 C. for 16 hours. The reaction mixture is shaken with dilute aqueous potassium hydroxide solution until the benzene layer is free of perbenzoic acid; the benzene layer is then washed with water until neutral, dried and the solvent evaporated in vacuo to give a crystalline material, 16a-methyl-17a,20-epoxypregnan-3u,20-diol-11-one 3,20-diacetate. The latter ma.- teri al is dissolved, without purification, in 200 ml. of methanol, 120 ml. of water and 10 grams of potassium bicarbonate added and the resulting solution is heated at reflux under nitrogen for a period of 16 hours. The methanol is evaported from the hydrolysis solution in vacuo and the residual oil is extracted from the resulting aqueous solution with chloroform. The chloroform extract is washed with Water to neutrality, dried and the chloroform is evaporated under reduced pressure. The residual oil is triturated with ether, and the crystalline material thus formed is recrystallized from ethyl-acetate- 10 petroleum ether to give 16a-methyl-pregnan 3wl7a-diol+ 11,20-dione.

To a solution of 7 grams of 16a-methyl-pregnan-3a, l7oz-dlOl-1L20-di0ne in 50 ml. of chloroform is added dropwise with stirring a solution containing 3.36 grams of bromine in 24.2 ml. of chloroform over a period of about 60 minutes. The reaction mixture is dissolved in 200 ml. of ethyl acetate, and the resulting solution washed with water until neutral, dried and the'solvents evaporated therefrom in vacuo. The residual crude material is dissolved in a minimum quantity of ethyl acetate, the resulting solution is diluted with ether, and the mixture is stirred until crystals form. The crystalline product is recovered by filtration and washed by slurrying with 50:50 ether-petroleum ether mixture to give about 5 grams of 21-bromo-16a-methyl-pregnan-3a,l7a-diol-11, 20-dione.

This 5 grams of 2l-bromo-l6a-methyl-pregnan-3a,17adiol1l,20-dione is mixed with 5 grams of anhydrous potassium acetate, 4 grams of sodium iodide and 0.03 ml. of glacial acetic acid, and ml. of acetone is added to the resulting mixture. This mixture is then heated at reflux, with stirring, for a period of about 16 hours, and the reaction mixture is cooled, filtered and the insoluble material is washed with acetone. The filtered solution is evaporated in vacuo thereby removing the solvents, and the residual material is slurriedwith water and the aqueous mixture extracted with ethyl acetate. The ethyl acetate extract is washed with Water to neutrality, dried and the solvent is evaporated in vacuo to give an oil. This oil is crystallized from ether, and recrystallized from ethyl acetate ether to give l6u-methyl-pregnan-3a,170:,21- triol-11,20-dione Ill-acetate.

A solution of 400 mg. of l6-a-methyl-pregnan-3a,17d, 2l-triol-ll,20-dione 2l-acetate in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg; of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed, and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and residual crystalline material is purified by crystallization from ethyl acetate to give l6a-methy pregnan-17a,21-diol-3,11,20-trione 2 I-acetate.

To 100 mg. of 1fia-rnethyl-pregnan-l7m,2l-diol-3,ll, 20-trione 2l-acetate dissolved in 2 ml. of chloroform and 2.25 ml. of glacial acetic acid, at a temperature of 55 C., is added two drops of 0.001 N solution of dry hydrogen bromide in glacial acetic acid. To about 0.38 ml. of 0.001 N hydrogen bromide in glacial acetic acid, at -55 C., is added 0.43 ml. of a solution containing 40 mg. of bromine in chloroform, and the resulting solution is added, over about a ten-minute period to the solution of the steroid while maintaining the reaction mixture at about 55 C. The reaction mixture is allowed to stand at -55 C. for about one-half hour; a solution containing 250 mg. of sodium acetate in 3 ml. of water is added, and the resulting mixture is stirred for about five minutes. 5 ml. of water are then added, and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with aqueous sodium bicarbonate solution to neutrality, then with Water, dried, and the solvent is evaporated in vacuo. The residual material is dissolved in 2 ml. of acetone, and to the solution is added 25 mg. of sodium bromide and 1 ml. of Water. The resulting mixture is heated under reflux for a period of about five hours, the reaction mixture is cooled and the acetone is evaporated in vacuo. The residual material is extracted into ether, the ether extract is washed with Water, dried and the solvent is evaporated to a volume of about 1 ml.; petroleum ether is added to this solution and the crystalthen washed and dried ethyl acetate extract evaporated to dryness in vacuo. The residual material is crystallized from methanol and recrystallized from ethyl acetate to give, 160: methyl 4 pregnen-17d,21-diol-3,11,20-trione 3(-isemicarbazone 21-acetate; melting point 225-228 C. ec.). i

A solution of 90 mg. of l6a-methyl-pregnen-l7a,21- diol-3,l1,20-trione-3-semicarbazone, 1.0 ml. of pyruvic acid,'l.0 ml. of glacial acetic acid and 1.0 ml. of water is allowed to stand for 20 hours at room temperature. The reaction solution is poured into 8 ml. of Water and the aqueous mixture is extracted with 40 ml. of chloroform in' six portions. The combined chloroform extract is washedwith an aqueous solution of sodium bicarbonatendried over sodium sulfate and evaporated in vacuo. The residual material is crystallized from acetone to give l6m-n1ethyl-4-pregnen-17:2,2 l-diol-3 ,l 1,20-trione.

16a-methyl substance S may be prepared from 16- pregnen-3a ol-20-one 3-acetate following the procedures described immediately above for making 16u-methyl cortisone from l6-pregnen-3a-ol-l1,20-dione 3-acetate. The intermediate products formed in synthesizing 16amethyll- 4 pregnen-3',20-dione-17ot,2l diol (l6a-methyl substance S) in this fashion are successively 16-methylpregnen-3a-ol-20-one 3-aeetate; 16oz methyl 17(20)- pregnen 30:,20 diol-3,20-diacetate; 16a-methyl-17a,20- epoxy-pregnen 301,20 diol 3,20-diacetate; l6m-methylpregnen-3a,17u-diol-20-one; 21-bromo-l6a-methyl-pregnan-3a,l7a-diol-20-one; l6a-methyl-pregnan 3a ,17a,21- triol-20-one Zl-acetate; 16m-methyl-pregnan-l7u,21-diol- 3,20-dione 2l-acetate; 4-bromo 16oz methyl-pregnanl7a,2l-diol-3,20-dione 21-acetate and 16a-methyl-4-preg V nen l'Za,2l-diol-3,20-dione 3 -semicarbazone 21-acetate. n

EXAMPLE 13 To a solution of 500 mg. of 16 3-methyl-17-20,20-2l bismethylenedioxy-3-ethylendioxy-5a,6a-oxido allopregnane-llB-ol in 115 ml. of dry benzene under nitrogen is added 5 ml. of 3 M methyl magnesium bromide in ether. The mixture is heated at 70 C. under nitrogen for four hours. After cooling to 5' G, 10 grams of ammonium chloride in 100 ml. of water is added over about a 30- minute period. The benzene is separated and the aqueous layer extracted with two 30 ml. portions of benzene. The combined benzene solutions are washed neutral with water, dried with magnesium sulfate and concentrated to dryness. The 618,16B-dimethyl-1720,20-21 bismethylenedioxy-3-ethylenedioxy allopregnan-a,llfi-diol thus obtained may be used in the next step of the process withoutfurther purification. It is purified, if desired, by recrystallization from ether or benzene.

EXAMPLE 14 55,1 6 fl-dimethyl-l 7-20,20-21 bismethylenea'iory-allopregnan-3-0ne-5a,11fi-diol i at reflux under-nitrogen for 30 minutes. The mixture is then cooled to Q- 5 C. and with cooling and strong agitation a solution of 6 grams of sodium carbonate in 150 ml. or water is added. The resulting precipitate is extracted with chloroform, washed with water, and ,concen- 'tratedreveals to dryness. The 6;3,16 8-dimethyl-l7-20, -21 bis meth'y1enedioxy allopregnan-3-one-5u,1lfi-diol thus" obtained is used directly in the next reaction: It ma y-be recrystallized from a lower alkanol to give substantially pure material. V

. EXAMPLE 15 p 6a,]6fi dimethyl-17-20,Z0-21 bismethylenedioxy-4-preg- Y nan-3-0ne-115-ol g A solution of one gram of 6 B,l6 8-dimethyl-l7-20,20-2l bism'ethylenedioxy-allopregnan-3-one-5u,llfl-diol in '50 ml. of methanol is purged with nitrogen and then 2'ml.

. of 5% potassium hydroxide in methanol is added slowly.

After repui'gin'g' with nitrogen, the solution is refluxed under nitrogen for one hour. It is then cooled to 20 C. and acidified with a'few drops of glacial acetic acid. 15 ml. of wateris added and the solution concentrated in 'vacuo until essentially solvent-free. The slightly yellow product thus obtained is filtered,- washed with water and dried to give 6m,16fl-dimethyl-17-20,20-21 bismethylenedioxy-4 pregnen-3-on'ed15-01. v V 3 V 7 EXAMPLE 16 6a,]6,8-dimethyl-4-pregnene-3,20-di0ne-1118,1 7oz,21-Iri0l A slurry of one gram of 6a,16,8-dirnethyl-l7-20,20-2l bismethylenedioxy-4-pregnen-3-one-1118-01in 97- ml. of 60% formic acid'is purged with nitrogen and then heated on}a steam bath at about C. for 15 minutes under nitrogen. I Thesolution is then cooled in an ice bath and 100 ml of'water added. Twenty grams of sodium car'- bonate are added slo'wly over 20 minutes.' The resulting precipitate is extracted with chloroform, the chloroform solution washed acid free with saturated sodium bicarbonate solution and then with water. The chloroformis removed in vacuo and'the residue flushed with-2 0 ml. of methanol and concentrated in vacuo to dryness.

The solid material obtained above is dissolvedin 45 ml. of purified methanol and purged with nitrogen. After adding 1.5 ml. of 0.21 M sodium methoxide in methanol, the solution is stirred for about 7 minutes at 2025 C. under nitrogen, 'The solution is then acidified with acetic acid, 5 ml. of water and 500 mg. of activated charcoal added and the mixture stirred at room temperature for 20 minutes. After filtering ofi the carbon, 40 m1. of water is added and the solution concentrated in vacuo. 'Ihesolid is filtered and dried to give 6a,l6,B-dimethyl-4- pregnene 3,20 dione-11fl,17a,2l-triol (6u,l6fl-dimethyl hydrocortisone). I

C-2l esters of 6a,l6 3 -dimethyl hydrocortisone are prepared by reacting the free alcohol with an acylating agent such as a lower 'alkanoic acid anhydride or a lower alkanoyl halide. The C 2l acetateis obtained by adding 0.1 gram of 6a,16fi-dimethyl hydrocortisone to 1 'ml. of acetic anhydride and 1 ml. of pyridine. The resulting mixture is warmed on a steam bath for 20'minutes then cooled and poured into 5 m1. ofcold water. Theaqueous solution is extracted twice with an equal volume-of chloroform, the chloroform solution washed with water and dried, and the chloroform then removed in vacuo to give substantially pure 6u,l6/8-dimethyl' hydrocortisone acetate. f l v Other esters such as the propionate, t-butylacetate, benzoate, phosphate and the like are prepared in a similar fashion using the appropriate acylatingagent.

-EXAMPLE 17 Q 65,16fi-dimethyl-1 7-20,.20-21 bismethylenedioxy-3 ethyl- V enedioxymllopregnan-I1-0ne-5a-ol I Two grams of l6B-methyl-17-20,20-.21.bismethylenedioxy-3-ethyl'enedioxyl- 5i,-6aoxido allopregnanvl'l one is dissolved in 450 ml. of benzene and the solution purged with nitrogen. To the resulting solution is added 18 ml. of 3 M methyl magnesium bromide, and the resulting mixture stirred at 70 C. in a nitrogen atmosphere for six hours. It is then cooled to 5 C. and 450 ml. of aqueous ammonium chloride slowly added over about 30 minutes. The resulting layers are separated and the aqueous layer extracted twice with small portions of benzene. All of the benzene solutions are then combined, washed with three 100 ml. portions of water, dried over magnesium sulfate and concentrated to dryness in vacuo. The resulting 6,9,16/3-dimethyl-17-20,20-21 bismethylenedioxy 3 ethylene dioxy-allopregnan-l l-one- Sa-Ol may be used in the next step of the process without purification.

EXAMPLE l8 6 0a,] (iii-dimethyl-J 7 -20,20-21 bismethyIenedi0xy4-pregnene-3,11-dione (a) 500 mg. of the product of Example 17 is dissolved in 30 ml. of methanol and the solution purged with nitrogen. Two m1. of 10% aqueous sulfuric acid is then added slowly and the mixture refluxed under nitrogen for about 35 minutes. The solution is cooled to 0-5 0, and treated with 2 grams of sodium carbonate in 50 ml. of water. The sodium carbonate solution is added slowly over a -minute period. 65,16B-dimethyl-17-20, 20-21 bismethylenedioxy-allopregnan 3,11 d'ione-5a-ol precipitates at this point. The slurry of steroid is cooled and the solid recovered by filtration.

(b) The material obtained in part (a) above is dissolved in ml. of methanol and to this solution is added one ml. of 5% methanolic potassium hydroxide. The resulting solution is refluxed in an inert atmosphere for one hour. It is then cooled and acidified with glacial acetic acid. The solution is then concentrated in vacuo and the residual solid dissolved in chloroform, and washed with sodium bicarbonate solution and water. The chloroform solution is dried over magnesium sulfate and concentrated to dryness in vacuo. The residual 6c,l6,B-dl methyl-17,20,20-21 bismethylenedioxy-4-pregnene 3,11- dione crystallizes on standing, and is converted to 601,165- dimethyl cortisone by treatment with 60% formic acid at 80 C. for thirty-five minutes.

EXAMPLE v19 When the process of Examples 13-16 are carried out employing 16,9-methyl-17-20,20-2 1 bismethylene-dioxy-3- ethylenedioxy 5a,6u oxido allopregnane-llB-ol as the starting material of Example 13, there is obtained 604,16 dimethyli-pregnen-17e,21-diol-3,20-dione.

The 16[3-methyl-17-20,20-21 bismethylenedioxy-3-ethylenedioxy-5a,6e-oxido-1l-oxygenated allopregnanes employed as starting materials for making the 16,8-methyl compounds of this invention are prepared as follows:

To a solution of 3a-acetoxy-16-pregnene-11,20-dione in a mixture of tetrahydrofuran and ethyl ether is added diazomethane to produce 3a-acetoxy-l6u,Not-methyleneazopregnane-11,20-dione (melting point 186190 C.) which precipitates from solution. Heating this compound at about 180 C. in vacuo produces 3a-acetoxy-16-methyl- 16-pregnene-11,20-dione (melting point 165167 C.) which upon reaction with hydrogen peroxide in the presence of sodium hydroxide in methanol solution for 18 hours at room temperature affords 16a,17a-epoxy-3ahydroxy 16B methyl pregnane 11,20 dione (melting point 178180 C.). When this compound is treated with perchloric acid in aqueous dioxane at 25-30 C. for 65 hours and the resulting reaction mixture is diluted with water, a mixture of 3a,17a-dihydroxy-16-methyl-15- pre nene 11,20-dione and 3a,l7u-dihydrcxy-l6-methylene-pregnane (melting point 158167 C.) is precipitated and recovered by filtration. Reduction of this mixture with hydrogen in methanol in the presence of palladiumcalcium carbonate catalyst affords a mixture of 3a,17adihydroxy-loa-methyl-pregnane 11,20-dione and ,17a-

14 dihydroxy-l6fi methyl-pregnane 11,20-dione sintering at C. Bromination of this mixture with bromine in chloroform at 40-45" C. affords a mixture of Zl-bromo- 3oz,17a-dihydroxy-16a-rnethyl pregnane-11,20 dione and 21-bromo-3u,17ot-dihydroxy 16 3-methyl-pregnane-1L20- dione which upon reaction with potassium acetate and potassium iodide in acetone produces a mixture of 3a,17a,2l trihydroxy-l6fl-methyl' pregnane 11.20- dione 21-acetate and 3a,17a,2l-trihydroxylfia-methylpregnane-11,20-dione 21-acetate. To a solution of this mixture in aqueous t-butanol at 1015 C. is added N- bromosuccinimide to produce a mixture of 17a,21-dihydroxy-l6a-methyl-pregnane-3,11,20-trione 2l-acetate and 17a,21-clihydroxy-l6B-methyl-pregnane-3,l1,20-trione 21- acetate which on chromatography on neutral alumina and elution with chloroform-benzene (1:1) and benzene yields 17a,21-dihydroxy-l6fi-methyl-pregn'ane-3J 1,20-trione ZI-acetate (melting point 2l0213 C.). Reaction of this compound with bromine in a mixture of acetic acid and chloroform affords the corresponding 4-bromo compound (melting point 170 C. dec.) which is converted by reaction with semicarbazide to a 3-semicarbazone of l7u,2l dihydroxy-16,8-methyl-4-pregnene- 3,11,20-trione 21-acetate. .Treatment of this compound with a mixture of acetic acid and pyruvic acid gives 17d,- 21 dihydroxy-16fl-methyl-4-pregnene 3,11,20-trione 21- acetate (melting point 226232 C.). This latter substance is then hydrolyzed to the C-21 free alcohol by treatment with potassium bicarbonate or potassium hydroxide in aqueous methanol. Such compounds are described in more detail in the copending application of Taub et a1. Serial No. 722,390, filed March 19, 1958.

Ten grams of 16fl-methyl-4-pregnen-l7a,21-diol-3,11, 20-trione are dissolved in 400 cc. of chloroform. To this solution is added a mixture of 100 cc. of 37% aqueous formaldehyde solution. The resulting mixture is stirred for a period of approximately three days at room temperature. The chloroform layer is separated, washed with sodium bicarbonate solution until neutral, then with water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residual crude material is purified by crystallization from a mixture of methylene chloride and methanol to give 17-20,20-21 bismethylenedioxy-l6fl-methyl 4-pregnene-3,1l-dione, which is substantially pure.

17.5 grams of 16/3-methyl-17-20,20-21 bismethylenedioxy cortisone is dissolved in 890 m1. of benzene, 45 ml. of ethylene glycol and 1.78 grams of p-toluene sulfonic acid, and the mixture heated at refiux for 17.5 hours. During this time a water separator is used to remove the water as it distills. The reaction mixture is then cooled to 20 C., washed with two 200 cc. portions of water, 200 cc. of saturated sodium bicarbonate solution and 200 cc. of'water. The organic layer is dried over anhydrous magnesium sulfate and concentrated to a solid. The solid after trituration with ether yields 12.4 grams of 16,8-methyl-17-20,20-21 bismethylenedioxy-3-ethylenedioxy-5-pregnen-l l-one.

To a stirred solution of two grams of lithium aluminum hydride in 200 ml. of dry tetrahydrofuran under nitrogen is added a solution of twograms of 16/3-methyl-17-20,20- 2 1 bismethylenedioxy-3-ethylenedioxy-S-pregnen-1 1 -one in 100 ml. of tetrahydrofuran. The reaction mixture is stirred and refluxed for two hours and then cooled to 5 C. Ethyl acetate (50 ml.) is added cautiously followed by 50 ml. of saturated sodium sulfate solution and then 50 grams of anhydrous magnesium sulfate. The mixture is filtered and the inorganic precipitate washed with ethyl acetate; the combined washings and filtrate are taken to dryness in vacuo to yield-a residue consist ing primarily of 16B-methyl-17-20,20-21 bismethylenedioxy-3-ethylenedioxy-S-pregnene-1 1 5-01.

A solution of '10 grams of 16 8-methyl-'17-20,20-21 bismethylenedioxy-3-ethylenedioxy-l1-R-5-pregnene (where R is keto or hydroxy) in 100 m1. of benzene is added to games 225 ml. of 0.325 M perbenzoic acid solution over about 30 minutes keeping the temperature 20-25 C. After 48 hours at room temperature, the solution is cooled to 10 C. and with good agitation a 15 solution of sodium bisulfite added at less than 20 C. until 'a negative KI test is obtained. The aqueous phase is removed and the benzene washed acid free'with sodium bicarbonate and then washed with water. After drying, the benzene solution is concentrated in vacuo to yield a mixture of 50560: and 55,6B-oxides.

One gram of the mixed oxides is chromatographed on 100 grams of fluorosil. Elution with 5% acetone in hexane gives the B-oxide. The a-oxide, 16fi-methyl-17-20,20- 21 bismethylenedioxy-3-ethylenedioxy-5a,6a-oxido-1l-R- allopregnane is eluted with acetone in hexane. In this fashion l6fl-methyl17-20,20-2l bismethylenedioxy- 3-ethylenedioxy-5u,6a-oxide-allopregnan-11,8-01 and 16pmethyl-17-20,20-21 bismethylenedioxy-3-ethylenedioxy- 5a,-6a-oxido-allopregnan-1l-one are prepared.

When 3a-acetoxy-l6-pregnen-20-one is put through the RI! 1 l OH CH:

that comprises treating a compound of the formula O'CH:

! /GH2 .0 v

with methyl magnesium halide, wherein R is selected from the class consisting of is a group 'convertibletoa keto group on hydrolysis.

and C=O and R- CH IT which comprises treating a compound of the formula l I 611 OH:

with a dilute mineral acid. wherein R is selected from the class consisting of 10. The process that comprises treating a compound of the formula &

with a strong base to producela compound of the formula wherein R is selected from the class consisting of and C= wherein R is selected from the group consisting of cH,, and

c=o and R" E is selected from the class consisting of keto and groups convertible thereto by hydrolysis.

15. 6,8,16fi-dimethyl-l7-20,20-2l bismethylenedioxy-3- ethylenedioxy-allopregnan-Sa,l l/S-diol.

16. 65,16fl dimethyl-17-20,20-21 bismethylenedioxyallopregnan-3-one-5 02,1 1 fi-diol.

17. 6,8,16fl-dimethyl-17-20,20-21 bismethylenedioxy-3- ethylenedioxy-allopregnan-l 1-one-5a-ol.

18. 65,165 dimethyl-17-20,20-2l bismethylenedioxyallopregnan-a, 1 1-dione-5a-ol.

18 19. Theprocessforzpreparing-a steroid-of' the formula o-on,

that comprises treating a compound of the formula O--CH:

with methyl magnesium halide, wherein R is selected from the class consisting of =0 and R" and is a group convertible to a keto group on hydrolysis.

20. The process for preparing 6fi,l6fi-dimethyl-17-20, 20-21 bismethy1enedioxy-3-ethylenedioxy-allopregnan-5a, llfl-diol that comprises treating 16-methyl-17-20,20-21 bismethylenedioxy 3 ethylenedioxy-5a,6u-oxido-allopregnane-l lfi-ol with methyl magnesium halide.

21. The process that comprises treating a compound of the formula with a strong base to produce a compound of the formula o-c-o 22. The for preparing 6u,16,8 dimethy1-17-20, 20 21 bismethylenedioxy-4-pregnen-3-one-115-01 that comprises heating a solution of 6fl,16fl-din1ethyl-17-20,20

21 bismethylenedioxy-allopregnan-3one-5a,1lp-diol in the 10 presence of an alkali metal hydroxide 23. The process for preparing 6a,'16p-dimethyl-17-20,

, I 20 20-21 bisniethylenedioxy-kpreghene-S,l'hdione:that cemprises heating a solution of 6,l6p-dimethyl-17-20,20-21 bismethylenedioxy-allopregnan-Ii,1l-dione-Sa-ol in the presence of an alkali metal hydroxide.

References Citeil in the file of this patent Spero et 111.2178; :1 .A.C.S., 6213-14 (1956). Beyleret a1.: 80, I.A.C.S., 1517-18 (1958); Arth et al.: 80, J.A.C.S 3160- -62 (1958). Oliveto et 211.: 80, J.A.C.S., 4428 (1958). Taub et 31.: 80, J.A.C.S., 4435 (1958). 

1. 6B, 16A-DIMETHYL-17-20,20-21 BISMETHYLENEDIOXY-3ETHYLENEDIOXY-ALLOPREGNAN-5A-OL.
 14. A COMPOUND OF THE FORMULA 